P698: BOSUTINIB DOSE OPTIMIZATION IN THE SECOND-LINE TREATMENT OF ELDERLY CML PATIENTS: EXTENDED 3-YEAR FOLLOW-UP AND FINAL RESULTS OF THE BEST STUDY
Authors: F. Castagnetti, M. Bocchia, E. Abruzzese, I. Capodanno, M. Bonifacio, G. Rege Cambrin, M. Crugnola, G. Binotto, C. Elena, A. Lucchesi, M. Bergamaschi, F. Albano, L. Luciano, F. Sorà, F. Lunghi, F. Stagno, M. Cerrano, A. Iurlo, A. R. Scortechini, S. Leonetti Crescenzi, R. Spadano, E. Trabacchi, M. Lunghi, G. Spinosa, D. Ferrero, D. Rapezzi, M. Ladetto, L. Nocilli, G. Gugliotta, M. Iezza, M. Cavo, G. Saglio, F. Pane, G. Rosti
Journal: HemaSphere (2022)

Background: The median age of CML patients requiring a second-line treatment is older than 60 years and many of these patients have relevant comorbidities. Bosutinib (BOS) is a second-generation TKI, with similar efficacy to dasatinib and nilotinib, but more favorable toxicity profile in the elderly, because of lower incidence of cardiovascular (CV) adverse events (AEs). BOS safety profile may be an added value in this setting, but a fixed initial dose of 500 mg OAD may be higher than necessary. Aims: All TKIs have been approved in CML at a specific initial dose, with dose reductions only in case of toxicity. The aim of our study was to evaluate the efficacy of low-dose BOS in the second line treatment of elderly CML patients, with subsequent dose increase only in patients without optimal molecular response at given timepoints (dose optimization). Methods: A prospective phase 2 single-arm study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: all patients, ≥ 60 yrs old, started BOS 200 mg for 2 weeks ("run-in" period), then the dose was increased to 300 mg; after 3 months, pts with BCR-ABLIS transcript ≤ 1% continued 300 mg, while in pts with transcript > 1% the dose is furtherly increased to 400 mg, in absence of relevant toxicity. The primary endpoint was the rate of MR3 at 12 months (core phase), but all pts were followed for additional 2 years (extension phase) to describe the long-term efficacy and outcome. Results: Sixty-three pts have been enrolled. Median age: 73 yrs (range 60-90). Reasons for switching to BOS: intolerance 65%, resistance 35%. First-line TKI: imatinib 83%, DAS 11%, NIL 6%. The rate of pts in MR3 at 12 mos was 59% (already reported). Median follow-up 38 mos (range 35-59). Maximum BOS dose: 400 mg, 21%; 300 mg, 73%; 200 mg, 6%. The probabilities of achieving or maintaining MR3, MR4 and MR4.5 by 36 mos were 78%, 54% and 46%, respectively (excluding pts with response at baseline, 73%, 50% and 44%, respectively); the probabilities were lower in the resistant cohort (64%, 36% and 18%, respectively). Overall, 24%, 33% and 11% of pts had 1 log, 2 logs or ≥ 3 BCR-ABLIS transcript logs reduction from baseline (68% of pts had a molecular improvement from baseline). At 36 mos, 36 pts (57%) were still on BOS (33 pts in optimal response, 3 pts in MR2), while 27 pts (43%) discontinued the study drug. Events leading to permanent treatment discontinuation: 7 CML unrelated deaths, 9 AEs (transaminase increase in 5 pts, skin rash, myalgia, GI toxicity and renal failure in 1 patient each), 9 unsatisfactory responses (without progression to advanced phases), 1 treatment-free remission attempt, 1 other reason. The overall survival probability was 81%. Pts with CV AEs: acute coronary syndromes, 6 pts; pericarditis, 2 pts; peripheral arterial thrombosis, 1 pt (all pts had CV risk factors). No pleural effusions were observed. The incidence of GI toxicity was lower than reported elsewhere. Thirty-six pts were still on BOS at the last contact: 6% on 400 mg, 50% on 300 mg, 44% on 200 mg. Image:Summary/Conclusion: A progressive dose increase, based on molecular response, in elderly CML patients treated with second-line bosutinib produced high response rates; few patients required a dose increase to 400 mg, while most pts remained on 300 mg or less. Not unexpectedly, given the old age, unrelated CV AEs and deaths occurred, but the study drug was generally well tolerated. An initial use of low dose TKIs, with dose optimization in case of absence of optimal response, is a promising strategy in elderly patients.